NMR polarization monitoring coils, hyperpolarizers with same, and methods for determining the polarization level of accumulated hyperpolarized noble gases during production

ABSTRACT

Hyperpolarizers which produce hyperpolarized noble gases include one or more on-board NMR monitoring coils configured to monitor the polarization level of the hyperpolarized gas at various production points in the polarized gas production cycle. A dual symmetry NMR coil is positioned adjacent the optical pumping cell and is in fluid communication with a secondary reservoir in fluid communication with the polarized gas dispensing or exit flow path. This can measure the post-thaw polarization of the gas “on-board” the polarizer. Alternately or additionally, a NMR monitoring coil is assembled to the exit port portion of the optical pumping cell to give a more reliable indication of the polarization level of the gas as it flows out of the gas optical pumping cell. Another NMR monitoring coil can be positioned in a cryogenic bath adjacent a quantity of frozen polarized  129 Xe to determine the polarization level of the frozen gas.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 09/344,000filed Jun. 30, 1999, now U.S. Pat. No. 6,295,834. The contents of thisdocument are hereby incorporated by reference as if recited in fullherein.

FIELD OF THE INVENTION

The present invention relates to the collection and accumulation ofpolarized noble gases, and relates more particularly to thedetermination of the level of polarization of hyperpolarized gases usedin NMR and magnetic resonance imaging (“MRI”) applications.

BACKGROUND OF THE INVENTION

It has recently been discovered that polarized inert noble gases canproduce improved MRI images of certain areas and regions of the bodywhich have heretofore produced less than satisfactory images in thismodality. Polarized helium-3 (“³He”) and xenon-129 (“¹²⁹Xe”) have beenfound to be particularly suited for this purpose. Unfortunately, as willbe discussed further below, the polarized state of the gases aresensitive to handling and environmental conditions and can, undesirably,decay from the polarized state relatively quickly. Further, because ofthe sensitivity of the polarized gas, it is desirable to monitor thepolarization level of the gas at various times during the product'slife. For example, in-process monitoring can indicate the polarizationachieved during the optical pumping process (described below) or thepolarization lost at certain phases of the life cycle process (so as todetermine the remaining useable life of the polarized gas or to helpidentify critical production path issues).

Hyperpolarizers are used to produce and accumulate polarized noblegases. Hyperpolarizes artificially enhance the polarization of certainnoble gas nuclei (such as ¹²⁹Xe or ³He) over the natural or equilibriumlevels, i.e., the Boltzmann polarization. Such an increase is desirablebecause it enhances and increases the MRI signal intensity, allowingphysicians to obtain better images of the substance in the body. SeeU.S. Pat. No. 5,545,396 to Albert et al., the disclosure of which ishereby incorporated herein by reference as if recited in full herein.

In order to produce the hyperpolarized gas, the noble gas is typicallyblended with optically pumped alkali metal vapors such as rubidium(“Rb”). These optically pumped metal vapors collide with the nuclei ofthe noble gas and hyperpolarize the noble gas through a phenomenon knownas “spin-exchange.” The “optical pumping” of the alkali metal vapor isproduced by irradiating the alkali-metal vapor with circularly polarizedlight at the wavelength of the first principal resonance for the alkalimetal (e.g., 795 nm for Rb). Generally stated, the ground state atomsbecome excited, then subsequently decay back to the ground state. Undera modest magnetic field (10 Gauss), the cycling of atoms between theground and excited states can yield nearly 100% polarization of theatoms in a few microseconds. This polarization is generally carried bythe lone valence electron characteristics of the alkali metal. In thepresence of non-zero nuclear spin noble gases, the alkali-metal vaporatoms can collide with the noble gas atoms in a manner in which thepolarization of the valence electrons is transferred to the noble-gasnuclei through a mutual spin flip “spin-exchange.” In any event, afterthe spin-exchange has been completed, the hyperpolarized gas isseparated from the alkali metal prior to introduction into a patient (toform a non-toxic pharmaceutically acceptable product). Unfortunately,both during and after collection, the hyperpolarized gas can deteriorateor decay relatively quickly (lose its hyperpolarized state) andtherefore must be handled, collected, transported, and stored carefully.Thus, handling of the hyperpolarized gases is critical, because of thesensitivity of the hyperpolarized state to environmental and handlingfactors and the potential for undesirable decay of the gas from itshyperpolarized state.

Some accumulation systems employ cryogenic accumulators to separate thebuffer gas from the polarized gas and to freeze the collected polarizedgas. Co-pending and co-assigned U.S. patent application Ser. No.08,999,604 to Driehuys et al. describes a suitable accumulator andmethod of cryogenically collecting, freezing, and then thawing frozenpolarized xenon. The contents of this application are herebyincorporated by reference as if recited in full herein.

Conventionally, the level of polarization has been monitored at thepolarization transfer process point (i.e., at the polarizer or opticalcell) in a hyperpolarizer device or measured at a site remote from thehyperpolarizer after the polarized gas is dispensed from thehyperpolarizer. For example, for the latter, the polarized gas isdirected to an exit or dispensing port on the hyperpolarizer and intotwo separate sealable containers, a gas delivery container, such as abag, and a small (about 5 cubic centimeter) sealable glass bulb specimencontainer. This glass bulb specimen container is then sealed at thehyperpolarizer site and then carried away from the hyperpolarizer to aremotely located high-field NMR spectroscopy unit (4.7 T) to determinethe level of polarization achieved during the polarization process. SeeJ. P. Mugler, B. Driehuys, J. R. Brookeman et al., MR Imaging andSpectroscopy Using Hyperpolarized 129Xe Gas; Preliminary Human Results,Mag. Reson. Med. 37, 809-815 (1997).

Generally stated, as noted above, conventional hyperpolarizers may alsomonitor the polarization level achieved at the polarization transferprocess point, i.e., at the optical cell or optical pumping chamber. Inorder to do so, typically a small “surface” NMR coil is positionedadjacent the optical pumping chamber to excite and detect the gastherein and thus monitor the level of polarization of the gas during thepolarization-transfer process. The small surface NMR coil will sample asmaller volume of the proximate polarized gas and thus have a longertransverse relaxation time (T₂*) compared to larger NMR coilconfigurations. A relatively large tip angle pulse can be used to samplethe local-spin polarization. The large angle pulse will generallydestroy the local polarization, but because the sampled volume is smallcompared to the total size of the container, it will not substantiallyaffect the overall polarization of the gas.

Typically, the surface NMR coil is operably associated with low-fieldNMR detection equipment which is used to operate the NMR coil and toanalyze the detected signals. Examples of low-field NMR detectionequipment used to monitor polarization at the optical cell and to recordand analyze the NMR signals associated therewith include low-fieldspectrometers using frequency synthesizers, lock-in amplifiers, audiopower amplifiers, and the like, as well as computers.

In any event, it is now known that on-board hyperpolarizer monitoringequipment no longer requires high-field NMR equipment, but instead canuse lowfield detection techniques to perform polarization monitoring forthe optical cell at much lower field strengths (e.g., 1-100 G) thanconventional high-field NMR techniques. This lower field strength allowscorrespondingly lower detection equipment operating frequencies, such as1-400 kHz.

For applications where the entire hyperpolarized gas sample can belocated inside the NMR coil, an adiabatic fast passage (“AFP”) techniquehas been used to monitor the polarization of the gas in this type ofsituation. Unfortunately, in most production-oriented situations, thistechnique is not desirable. For example, in order to measure thepolarization in a one-liter patient dose bag, a relatively large NMRcoil and spatially large magnetic field is needed.

More recently, Saam et al. has proposed a low-frequency NMR circuitexpressly for the on-board detection of polarization levels forhyperpolarized ³He at the optical cell inside the temperature-regulatedoven which encloses the cell. See Saam et al., Low Frequency NMRPolarimeter for Hyperpolarized Gases, Jnl. of Magnetic Resonance 134,67-71 (1998). Magnetic Imaging Technologies, Inc. (“MITI”) and othershave used low-field NMR apparatus for on-board polarization measurement.

However, there remains a need to be able to efficiently and reliablydetermine and/or m6nitor the level of polarization of polarized gases invarious points in the production cycle. This is particularly importantfor the flowing production modality used for cryogenically accumulated¹²⁹Xe, which as noted above, is frozen and thawed during the productioncycle.

OBJECTS AND SUMMARY OF THE INVENTION

In view of the foregoing, it is an object of the present invention toprovide methods and apparatus to efficiently monitor thehyperpolarization level of a quantity of hyperpolarized gas at variouspoints in the production cycle.

It is an additional object of the present invention to provide ahyperpolarizer with means to monitor the polarization level ofcryogenically accumulated hyperpolarized gas both before the gas isfrozen and after the gas is thawed.

It is another object of the present invention to provide a method anddevice for monitoring the polarization level of flowing hyperpolarizedgas which can be used in a substantially continuous gas-flow productionenvironment.

It is a further object of the present invention to provide an apparatusand method which reduces the complexity and number of components neededto monitor the level of polarization in the polarized gas both duringthe optical pumping process and subsequent to the optical pumpingprocess.

It is still another object of the present invention to provide anapparatus to monitor the polarization level of frozen polarized gas.

It is an additional object of the present invention to provide anapparatus that can improve the predictability of a cryogenichyperpolarized gas production process.

It is a still further object of the present invention to provide anapparatus that can reliably yield sufficient levels of polarized gasduring post accumulation thaw.

These and other objects are satisfied by the present invention by ahyperpolarizer apparatus with one or more NMR coils configured toprovide “on-board” polarization monitoring level information at morethan one point during the production cycle. In a preferred embodiment,the hyperpolarizer includes a dual symmetry NMR coil configuration whichallows the same NMR coil and detection circuit to be used to measure¹²⁹Xe polarization both in the optical cell before cryogenicaccumulation and in a post thaw bulb after cryogenic accumulationthawing.

In particular, a first aspect of the invention is directed to ahyperpolarizer for producing polarized noble gases. The hyperpolarizercomprises an optical pumping cell having a non-polarized gas inlet portand a polarized gas outlet port and a magnetic field source operablyassociated with the optical pumping cell. The magnetic field source isconfigured to provide a region of homogeneity. The hyperpolarizer alsoincludes a NMR coil having first and second opposing ends. The first endis positioned adjacent the optical pumping cell within the region ofhomogeneity. The hyperpolarizer also includes a cryogenic accumulator influid communication with the optical pumping cell outlet port and apolarized gas dispensing port in fluid communication with the cryogenicaccumulator. A polarized gas exit flow path extends between saidcryogenic accumulator and the polarized gas dispensing outlet and asecondary reservoir is positioned adjacent the NMR coil second end influid communication with the polarized gas exit flow path. Duringoperation of the hyperpolarizer, the NMR coil is configured to exciteone of a quantity of polarized gas positioned in the optical cell and aquantity of polarized gas positioned in the secondary reservoir.Preferably, the NMR coil primarily monitors the polarization in theoptical cell during operation of the cell, but during post-thaw, thepolarization in the optical cell is gone and the only measurable signalwill arise from the polarized gas in the post thaw bulb.

In a preferred embodiment, the magnetic field source defines a region ofhomogeneity which includes a portion of the optical pumping cell and a(spatial) volume which extends a distance below the optical pumpingcell. The NMR coil is positioned on a bottom portion of the opticalpumping cell, and the NMR coil and at least a portion of the secondaryreservoir are positioned within the region of homogeneity.

Another aspect of the present invention is a secondary reservoir for ahyperpolarizer unit. The secondary reservoir is configured to hold aquantity of hyperpolarized noble gas therein and comprises opposingfirst and second end portions defining a gas flow path therebetween. Thefirst end portion is configured to capture a quantity of hyperpolarizedgas therein. The second end portion has an opening formed therein and isconfigured to engage with a portion of a (hyperpolarized) gas flow line.Preferably, the first end is configured with a thin wall.

An additional aspect of the present invention is a dual symmetry NMRcoil for monitoring the level of polarization associated with polarizedgas in two different locations. The dual symmetry NMR coil comprisesfirst and second opposing flanges and an intermediate coil sectionpositioned therebetween. The thickness of the first and second flangesare substantially the same.

Still another aspect of the present invention is a hyperpolarizer forproducing polarized noble gases. The hyperpolarizer comprises an opticalpumping cell having a primary body and a longitudinally extendingpolarized gas outlet port with an outer surface. The hyperpolarizerincludes a magnetic field source operably associated with the opticalpumping cell. The magnetic field source is configured to provide aregion of homogeneity. The hyperpolarizer also includes a first NMR coilhaving first and second opposing ends and defining a center aperturetherethrough. The first NMR coil is positioned on the outlet port suchthat the outlet port longitudinally extending portion extends throughthe first NMR coil aperture. The first end of the first NMR coil beingpositioned adjacent the primary body of the optical pumping cell withinthe region of homogeneity. During operation of the hyperpolarizer, thefirst NMR coil is configured to excite a quantity of polarized gaspositioned proximate to the optical cell outlet port. In a preferredembodiment, the hyperpolarizer includes a second and third NMRmonitoring coil positioned at other selected points in the productioncycle.

A preferred method of operating an NMR coil positioned proximate to theoptical cell outlet port, includes flowing the hyperpolarized gasthrough the optical cell and out the port at a desired rate. Thehyperpolarized gas flow is preferably temporally stopped or slowed and aNMR signal is taken via the coil on the outlet port (or arm) and theflow is then resumed. This configuration and method can generate asignal which is representative of the flowing hyperpolarized gas as itexits the optical cell.

Another aspect of the present invention is directed to anotherhyperpolarizer embodiment for producing optically pumped polarized noblegases. The hyperpolarizer comprises an optical pumping cell having anon-polarized gas inlet port and a polarized gas outlet port and aprimary body. The hyperpolarizer also includes a cryogenic accumulatorin fluid communication with the optical pumping cell outlet port. Thecryogenic accumulator comprises an elongated closed end tube defining apolarized gas collection chamber for holding a quantity of collectedpolarized gas therein. The gas collection chamber is operably associatedwith first and second sealable valves. The cryogenic accumulator alsoincludes a cryogenic bath, wherein the collection chamber is immersedinto the cryogenic bath. The cryogenic accumulator also includes a setof permanent magnets arranged to provide a magnetic field with a regionof homogeneity adjacent the collection chamber in the cryogenic bath anda first NMR coil positioned in the cryogenic bath adjacent the closedend of the tube in the magnetic field region of homogeneity. Thehyperpolarizer also includes a polarized gas dispensing outlet in fluidcommunication with the cryogenic accumulator and a polarized gas exitflow path extending from the cryogenic accumulator to a polarized gasdispensing outlet. During operation of the hyperpolarizer, the first NMRcoil is configured to monitor the level of polarization in the polarizedgas in the closed end of the collection tube.

Yet another aspect of the present invention is a method for monitoringthe polarization level of polarized gas during production. The methodincludes polarizing a quantity of noble gas in an optical pumpingchamber and directing the polarized noble gas in the optical pumpingchamber to a gas collection path. A magnetic field having a region ofhomogeneity is provided; the region of homogeneity preferably includesat least a volume of space associated with a portion of the opticalpumping chamber and the gas collection path proximate to the opticalpumping chamber. A first NMR coil is positioned adjacent the gas flowpath in the magnetic field region of homogeneity and the polarized gasis excited by transmitting an excitation signal to the first NMR coil.The level of polarization associated with the hyperpolarized gasadjacent to the NMR coil is measured to thereby monitor the level ofpolarization associated with the polarized gas in a region of thepolarizer adjacent the polarized gas flow path.

In a preferred embodiment, the optical pumping chamber has a primarybody portion and a polarized gas exit port defined by a longitudinallyextending leg, and the NMR excitation coil is positioned around the legadjacent the primary body portion of the optical pumping chamber. It isalso preferred that the method further comprise cryogenicallyaccumulating the polarized gas in a cryogenic accumulator during which aportion of the polarized gas is frozen and then subsequently thawing thefrozen polarized gas prior to the dispensing step and after the thawingstep. It is also preferred that during or after the thawing step, aminor portion of the quantity of thawed polarized gas is directed awayfrom a major portion of the hyperpolarized gas into the gas flow pathproximate to the NMR coil.

Yet still another aspect of the present invention is directed to ahyperpolarized gas optical pumping cell having an integrated NMR coil.The integrated cell includes an optical pumping cell which has a primarybody and at least one longitudinally extending leg portion. Theintegrated cell also includes a NMR coil having opposing first andsecond ends and an aperture formed through the center thereof. The firstend is configured to receive a portion of said longitudinally extendingleg therein and attach to the optical pumping cell. Preferably, the NMRcoil attaches to the leg adjacent the primary body along the gas exitflow path.

It is an additional aspect of the present invention to provide a methodfor releasing the post-thaw cryogenically accumulated hyperpolarized gasin a hyperpolarizer having a cold finger collection container and exitflow path plumbing associated therewith. The method includes the stepsof cryogenically accumulating a quantity of frozen hyperpolarized gas ina cold finger and monitoring a pressure associated with thecryogenically collected gas in the cold finger. (After cryogenicaccumulation, flow is stopped and residual gases are evacuated, and heatis applied to start the thaw). At least a portion of the quantity offrozen hyperpolarized gas in the cold finger is thawed. The pressure inthe cold finger is increased in response to the phase transition of thefrozen hyperpolarized gas from a substantially frozen sample into athawed fluid sample. The thawed hyperpolarized fluid sample is releasedas a gas from the cold finger responsive to a predetermined pressureassociated with the cold finger corresponding to said monitoring step.In a preferred embodiment, the frozen gas transitions directly to aliquid phase and releasing step is performed in response to the openingof a valve downstream of the cold finger in the hyperpolarizer and boththe thawing and releasing steps are performed on-board thehyperpolarizer.

Advantageously, the present invention can monitor the polarizationduring production and even at the dispensing port where convenient MRIpatient-sized quantities (such as 0.5-2 liters of polarized gas) aredirected out of the hyperpolarizer. As such, the polarization level atshipping or before storage is readily identifiable before the containeris detachably released from the hyperpolarizer unit for easy transportto a remote site. The improved on-board in-process polarizationmonitoring can improve production and conveniently indicate the level ofpolarization of gas at several key points including at the dispensingport. Further, the dual symmetry NMR coil can allow a single NMR coil tomeasure polarization both at the optical cell during the optical pumpingprocess and at a second point in the production cycle, such as at apost-thaw position. Further, the instant invention now configures a coldfinger to release cryogenically accumulated hyperpolarized xenondependent on a more predictable indicator, pressure. Because the releaseof the thawed gas at a predetermined pressure is less dependent onprocess variations such as flow rates and collected quantities of gas, amore predictable process can be obtained, thereby providing a morereliably controllable production capability.

The foregoing and other objects and aspects of the present invention areexplained in detail herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of a hyperpolarizer apparatusaccording to one embodiment of the present invention.

FIG. 2A is a side view of a dual symmetry NMR coil according to thepresent invention.

FIG. 2B is a side view of the NMR coil of FIG. 2A schematicallyillustrating the electrical wire wrapped around and positioned onto theNMR coil body.

FIG. 2C is a top view of FIG. 2A.

FIG. 3 is an enlarged perspective view of a secondary reservoiraccording to the present invention.

FIG. 3A is an enlarged perspective view of an alternate embodiment of asecondary reservoir according to the present invention.

FIG. 4 is a perspective view of a partial plumbing layout for ahyperpolarizer with a NMR coil and secondary reservoir according to thepresent invention.

FIG. 5 is a schematic diagram for an operational relationship of anelectrical monitoring circuit according to the present invention.

FIG. 6 is a schematic illustration of an alternate embodiment of ahyperpolarizer with multiple in process polarization monitoring pointsaccording to the present invention.

FIG. 7A is a front view of an optical cell and NMR coil illustrating theNMR coil positioned along the exit gas flow path of the optical cellaccording to one embodiment of the present invention.

FIG. 7B is an exploded view of the optical cell and NMR coil of FIG. 7Aillustrating a fabrication method for positioning a NMR monitoring coilalong the exit flow path of the hyperpolarizer of FIG. 6 according tothe present invention.

FIG. 8 is a schematic illustration of yet another embodiment of ahyperpolarizer with multi-point monitoring according to the presentinvention.

FIG. 9 is a schematic illustration of an additional embodiment of ahyperpolarizer according to the present invention illustrating acryogenically positioned NMR excitation coil.

FIG. 9A is an enlarged schematic illustration of the NMR coil configuredas a solenoid coil as shown in FIG. 9.

FIG. 10 is a schematic side section view of a cryogenically positionedNMR surface coil and externally positioned permanent magnets (i.e.,permanent magnets positioned on external to the cryogen bath) accordingto one embodiment of the present invention.

FIG. 11 is a schematic illustration of a front view of a static magneticholding field applied to an electromagnet or solenoid coil at the coldfinger according to one embodiment of the present invention.

FIG. 12 is a schematic illustration of an electric circuit for ahyperpolarizer with multi-NMR coils according to the present invention.

FIG. 13 is a graph illustrating prior art detection methods showing acomparison of a direct-detect FID with a typical mixed-down two channelFID.

FIG. 14 is a schematic illustration of a prior art NMR polarizationlevel detection circuit modified to add a circuit switching means tomonitor additional points in the production cycle according to thepresent invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will now be described more fully hereinafter withreference to the accompanying figures, in which preferred embodiments ofthe invention are shown. This invention may, however, be embodied inmany different forms and should not be construed as limited to theembodiments set forth herein. Like numbers refer to like elementsthroughout. In the drawings, layers, regions, or components may beexaggerated for clarity.

In the description of the present invention that follows, certain termsare employed to refer to the positional relationship of certainstrictures relative to other structures. As used herein the term“forward” and derivatives thereof refer to the general direction the gasmixture travels as it moves through the hyperpolarizer unit; this termis meant to be synonymous with the term “downstream” which is often usedin manufacturing environments to indicate that certain material beingacted upon is farther along in the manufacturing process than othermaterial. Conversely, the terms “rearward” and “upstream” andderivatives thereof refer to the directions opposite, respectively, theforward and downstream directions. Also, as described herein, polarizedgases are collected, frozen, thawed, and used in MRI applications. Forease of description, the term “frozen polarized gas” means that thepolarized gas has been frozen into a solid state. The term “liquidpolarized gas” means that the polarized gas has been or is beingliquefied into a liquid state. Thus, although each term includes theword “gas,” this word is used to name and descriptively track the gaswhich is produced via a hyperpolarizer to obtain a polarized “gas”product. Thus, as used herein, the term “gas” has been used in certainplaces to descriptively indicate a hyperpolarized noble gas product andmay be used with modifiers such as solid, frozen, and liquid to describethe state or phase of that product.

Various techniques have been employed to accumulate and capturepolarized gases. For example, U.S. Pat. No. 5,642,625 to Cates et al.describes a high volume hyperpolarizer for spin polarized noble gas andU.S. Pat. No. 5,809,801 to Cates et al. describes a cryogenicaccumulator for spin-polarized ¹²⁹Xe. These patents are herebyincorporated by reference as if recited in full herein. As used herein,the terms “hyperpolarize,” “polarize,” and the like, mean toartificially enhance the polarization of certain noble gas nuclei overthe natural or equilibrium levels. Such an increase is desirable becauseit allows stronger imaging signals corresponding to better MRI images ofthe substance and a targeted area of the body. As is known by those ofskill in the art, hyperpolarization can be induced by spin-exchange withan optically pumped alkali-metal vapor or alternatively by metastabilityexchange. See Albert et al., U.S. Pat. No. 5,545,396.

Referring to the drawings, FIG. 1 illustrates a preferred hyperpolarizerunit 10. This is a high-volume unit which is configured to produce andaccumulate spin-polarized noble gases substantially continually, i.e.,the flow of gas through the optical cell is substantially continuousduring accumulation. As shown, the unit 10 includes a noble gas mixturesupply 12 and a supply regulator 14. A purifier 16 is positioned in theline to remove impurities such as water vapor from the system as will bediscussed further below. The hyperpolarizer unit 10 also includes a flowmeter 18 and an inlet valve 20 positioned upstream of a polarizer oroptical cell 22. An optic light source such as a laser 26 (preferably adiode laser array) is directed into the polarizer cell 22 throughvarious focusing and light distributing means 24, such as lenses,mirrors, and the like. The laser 26 is circularly polarized to opticallypump alkali metals in the cell 22. The cell 22 is positioned inside atemperature-regulated oven (schematically illustrated by a double dottedline) 122. An additional valve 28 is positioned downstream of thepolarizer cell 22.

Next in line, as shown in FIG. 1, is a cold finger or accumulator 30.The accumulator 30 is connected to the hyperpolarizer unit 10 by a pairof releasable mechanisms such as threaded members or quick disconnects31, 32. This allows the accumulator 30 to be easily detached, removed,or added, to and from the system 10. The accumulator 30 is operablyassociated with a cold source or refrigeration means 42. Preferably, andas shown, the cold source 42 is a liquid cryogen bath 43. Theaccumulator 30 will be discussed in more detail hereinbelow.

As shown in FIGS. 1 and 9, the hyperpolarizer 10 also includes a vacuumpump 60 is in communication with the system. Additional valves tocontrol flow and direct exit gas are shown at various points (shown as52, 55). A shut-off valve 47 is positioned adjacent an “on-board” exitgas tap 50. Certain of the valves downstream of the accumulator 30 areused for “on-board” thawing and delivery of the collected polarized gasas will be described further below. A preferred accumulator or“cold-finger” is described in co-pending and co-assigned U.S.application Ser. No. 08/989,604 to Driehuys et al, the contents of whichis hereby incorporated by reference as if recited in its entiretyherein.

The unit 10 also includes a digital pressure transducer 54 and flowcontrol means 57 along with a shut-off valve 58. The shut-off valve 58preferably controls the flow of gas through the entire unit 10; it isused to turn the gas flow on and off, as will be described below. Aswill be understood by those of skill in the art, other flow controlmechanisms, and devices (analog and electronic) may be used within thescope of the present invention.

In operation, a gas mixture is introduced into the unit 10 at the gassource 12. As shown in FIG. 1, the source 12 is a pressurized gas tankwhich holds a premixed gas mixture. Generally described, forspin-exchange optically pumped systems, a gas mixture is introduced intothe hyperpolarizer apparatus upstream of the polarizer cell 22. Mostxenon gas mixtures include a buffer gas as well as a lean amount of thegas targeted for hyperpolarization and are preferably produced in acontinuous flow system. For example, for producing hyperpolarized ¹²⁹Xe,the premixed gas mixture is about 85-98% He (preferably about 85-89%He), about 5% or less ¹²⁹Xe, and about 1-10% N₂ (preferably about6-10%). In contrast, for producing hyperpolarized ³He, a typical mixtureof about 99.25% ³He and 0.75% N₂ is pressurized to 8 atm or more andheated and exposed to the optical laser light source, typically in abatch mode system. In any event, once the hyperpolarized gas exits thepolarizer cell (i.e., the pumping chamber) 22, it is directed to acollection or accumulation container.

Thus, as described above, in a preferred embodiment, the pre-mixed gasmixture includes a lean noble gas (the gas to be hyperpolarized) andbuffer gas mixture. The gas mixture is passed through the purifier 16and introduced into the polarizer cell 22. The valves 20, 28 are on/offvalves operably associated with the polarizer cell 22. The gas regulator14 preferably steps down the pressure from the gas tank source 12(typically operating at 2000 psi or 136 atm) to about 6-10 atm for thesystem. Thus, during accumulation, the entire manifold (conduit,polarized cell, accumulator, etc.) is pressurized to the cell pressure(about 6-10 atm). The flow in the unit 10 is activated by opening valve58 and is controlled by adjusting the flow control means 57.

The typical residence time of the gas in the cell 22 is about 10-30seconds; i.e., it takes on the order of 10-30 seconds for the gasmixture to be hyperpolarized while moving through the cell 22. The gasmixture is preferably introduced into the cell 22 at a pressure of about6-10 atm. Of course, as is known to those of skill in the art, withhardware capable of operating at increased pressures, operatingpressures of above 10 atm, such as about 20-30 atm, are preferred topressure broaden the alkali metal (such as rubidium (“Rb”)) andfacilitate the absorption of (approaching up to 100%) of the opticallight. In contrast, for laser linewidths less than conventionallinewidths, lower pressures can be employed. The polarizer cell 22 is ahigh pressure optical pumping cell housed in a heated chamber withapertures configured to allow entry of the laser emitted light.Preferably, the hyperpolarizer unit 10 hyperpolarizes a selected noblegas such as ¹²⁹Xe (or ³He) via a conventional spin-exchange process. Avaporized alkali metal such as Rb is introduced into the polarizer cell22. The Rb vapor is optically pumped via an optic light source 26,preferably a diode laser.

The unit 10 employs helium buffer gas to pressure broaden the Rb vaporabsorption bandwidth. The selection of a buffer gas is important becausethe buffer gas—while broadening the absorption bandwidth—can alsoundesirably impact the alkali metal-noble gas spin-exchange bypotentially introducing an angular momentum loss of the alkali metal tothe buffer gas rather than to the noble gas as desired. In a preferredembodiment, ¹²⁹Xe is hyperpolarized through spin exchange with theoptically pumped Rb vapor. It is also preferred that the unit 10 use ahelium buffer gas with a pressure many times greater than the 9Xepressure for pressure broadening in a manner which minimizes Rb spindestruction.

As will be appreciated by those of skill in the art, Rb is reactive withH₂O. Therefore, any water or water vapor introduced into the polarizercell 22 can cause the Rb to lose laser absorption and decrease theamount or efficiency of the spinexchange in the polarizer cell 22. Thus,as an additional precaution, an extra filter or purifier (not shown) canbe positioned before the inlet of the polarizer cell 22 with extrasurface area to remove even additional amounts of this undesirableimpurity in order to further increase the efficiency of the polarizer.

Hyperpolarized gas, together with the buffer gas mixture, exits thepolarizer cell 22 and enters a collection reservoir 75 located at thebottom of the accumulator 30. In operation, at the lower portion of theaccumulator 30, the hyperpolarized gas is exposed to temperatures belowits freezing point and collected as a frozen product 100 in thereservoir 75. The hyperpolarized gas is collected (as well as stored,transported, and preferably thawed) in the presence of a magnetic field,generally on the order of at least 500 Gauss, and typically about 2 kiloGauss, although higher fields can be used. Lower fields can potentiallyundesirably increase the relaxation rate or decrease the relaxation timeof the polarized gas. As shown in FIG. 1, the magnetic field is providedby permanent magnets 40 positioned in the cryogen bath and arrangedabout a magnetic yoke 41.

The hyperpolarizer unit 10 can also capitalize on the temperature changein the outlet line between the heated pumping cell 22 and therefrigerated cold trap or accumulator 30 to precipitate the alkali metalfrom the polarized gas stream in the conduit above the accumulator 30.As will be appreciated by one of skill in the art, the alkali metal canprecipitate out of the gas stream at temperatures of about 40° C. Theunit 10 can also include an alkali metal reflux condenser (not shown) orpost-cell filter (not shown). The refluxing condenser employs a verticalrefluxing outlet pipe which is kept at room temperature. The gas flowvelocity through the refluxing pipe and the size of the refluxing outletpipe is such that the alkali metal vapor condenses and drips back intothe pumping cell by gravitational force. Alternatively, a Rb filter canbe used to remove excess Rb from the hyperpolarized gas prior tocollection or accumulation. In any event, it is desirable to removealkali metal prior to delivering polarized gas to a patient to provide anon-toxic, sterile, or pharmaceutically acceptable substance (i.e., onethat is suitable for in vivo administration).

Once a desired amount of hyperpolarized gas has been collected in theaccumulator 30, the accumulator 30 can be detached or isolated from theunit 10. In a preferred embodiment, valve 28 is closed, leaving the cell22 pressurized. This allows the accumulator 30 and the downstreamplumbing to begin to depressurize because the flow valve 58 is open.Preferably, the portion of the unit 10 downstream of the valve 28 isallowed to depressurize to about 1.5 atm before the flow valve 58 isclosed. After closing the flow valve 58, valve 55 can be opened toevacuate the remaining gas in the manifold. Once the outlet plumbing isevacuated, valves 35 and 37 are closed. If the collected gas is to bedistributed “on-board,” i.e., without removing the accumulator 30 fromthe unit 10, a receptacle such as a bag 525 or other vessel as shown inFIG. 9, can be attached to the outlet 50. The valve 47 can be opened toevacuate the attached bag. Once the bag 525 is evacuated and the gas isready to thaw, valve 52 can be optionally closed. This minimizes thecontact of the polarized gas with the pressure transducer region 59 ofthe unit 10. This region can include materials that have a depolarizingeffect on the polarized gas. Thus, long contact times with this regionmay promote relaxation of the polarized gas.

If the valve 52 is not closed, then valve 55 is preferably closed toprevent the evacuation of polarized thawed gases. It is also preferredthat the flow channels on the downstream side of the cell 22 (includingthe secondary reservoir and bleed line discussed below) are formed frommaterials which minimize the contact-induced depolarization effect onthe polarized state of the gas. Coatings can also be used such as thosedescribed in U.S. Pat. No. 5,612,103, the disclosure of which is herebyincorporated by reference as if recited in full herein. Other suitablematerials are described in co-pending and co-assigned U.S. patentapplication Ser. No. 09/126,448 to Deaton et al. The content of thisapplication is also incorporated by reference as if recited in fullherein. In the “on-board” thaw operation, valve 37 is opened to let thegas out. It then proceeds through valve 47 and out outlet 50.

In the “detached” or “transported accumulator” thaw mode, accumulatorfirst and second isolation valves 35, 37 are closed after thedepressurization and evacuation of the accumulator 30. Evacuating theaccumulator 30 allows any residual gas in the accumulator 30 to beremoved. Leaving gas in the accumulator 30 with the frozen polarized gasmay contribute to the heat load on the frozen gas, possibly raising thetemperature of the frozen gas and potentially shortening the relaxationtime. Thus, in a preferred embodiment, after depressurization andevacuation and closing the isolation valves 35, 37, the accumulator 30is disconnected from the unit 10 via release points 31, 32.

The isolation valves 35, 37 are in communication with the primary flowchannel 80 and the buffer gas exit channel 90 respectively and each canadjust the amount of flow therethrough as well as close the respectivepaths to isolate the accumulator from the unit 10 and the environment.After the filled accumulator 30 is removed, another accumulator 30 canbe easily and relatively quickly attached to the release points 31, 32.Preferably, when attaching the new accumulator 30, the outlet manifoldis evacuated using valve 55 (with valves 52, 35, 37 open). When asuitable vacuum is achieved (such as about 100 mm Torr) which typicallyoccurs within about one minute or so, valve 55 is closed. Valve 28 isthen re-opened which repressurizes the outlet manifold to the operatingcell pressure. Valve 58 is then opened to resume flow in the unit 10.Preferably, once flow resumes, liquid nitrogen is applied to theaccumulator 30 to continue collection of the hyperpolarized gas.Typically such a changeover takes on the order of less than about fiveminutes. Thus, a preferred hyperpolarizer unit 10 is configured toprovide a continuous flow of hyperpolarized ¹²⁹Xe gas for continuousproduction and accumulation of same.

On-board Post-optical Cell Polarization Monitor

In prior polarization units, typically a NMR excitation coil waspositioned in the oven 122 adjacent the optical cell 22 (also in theoven) to determine the polarization level achieved by the gas in thecell 22. Further, at least one laboratory has also used a small sealable(about 5 cc) glass bulb which was filled with a sample of hyperpolarizedgas at the same point as the collection vessel or dose bag. The smallbulb was then taken to a separate 4.7 T spectrometer to determine thelevel of polarization associated with the collection vessel.

The present invention now conveniently provides for an on-board (on thehyperpolarizer unit 10) polarization level measurement associated withthe polarized gas at various points in the production cycle, such as atboth at the polarizer cell 22 and one or more pre-dispensing andpost-thaw gas production point(s). As shown in FIG. 1, in a preferredembodiment, the (post-thaw) gas exit path 113 (the gas exit pathillustrated in dotted line) starts at the cold finger accumulator 30,extends down the exit line 113 a to valve 47 and then to dispensingoutlet line 114. The dispensing-outlet line 114 ends at the xenon outlet50. A small bleed line 115 is in fluid communication with the xenonoutlet 50. Preferably, as shown in FIG. 1, the bleed line 115 isconnected to the dispensing outlet line 114 a distance above the xenonoutlet 50. However, the bleed line 115 can be alternatively positionedalong the exit line 113 a, but is preferably positioned adjacent thedispensing outlet 50 to provide a more reliable indication of thepolarized state of the gas at the outlet 50. The bleed line 115 is influid communication with the dispensing outlet line 114 and defines asecondary flow path for the hyperpolarized gas, the bleed line 115 beingconfigured and sized to direct a small quantity of the hyperpolarizedgas to the secondary reservoir 120.

In a preferred embodiment, a quantity of hyperpolarized gas iscryogenically accumulated as described above to collect a quantity ofhyperpolarized ¹²⁹Xe in frozen or ice form. Valves 35 and 37 are closed.The frozen hyperpolarized ¹²⁹Xe gas is then warmed, preferably byapplying heat and increasing the pressure in the accumulator 30 suchthat the solid transitions substantially directly to liquid phase.Typically, after about an eight second delay from the time of heatapplication, the xenon isolation valve 52 is closed and the accumulator30 is opened via valve 37 to allow the post thaw gas to enter the exitline 113 through gate 32. The hyperpolarized gas then flows throughvalve 47 into the dispensing outlet line 114 and a majority of the gasis directed to a collection vessel at the xenon outlet 50. During thisportion of the production cycle, valve 52 can remain open, but it ispreferred that valve 55 be closed for pressure monitoring.

Recently, the hyperpolarizer unit 10 has been reconfigured to operatewith potentially even more reliable thaws according to one aspect of thepresent invention. As discussed above, previous thaw methods haveprovided increased post-thaw polarization levels. Referring to FIG. 9,in this previous method, both cold finger valves 35, 37 were closed anda waiting period (typically set at about 8 seconds) was employed beforeone or more of the valves 35, 37 were opened to release the gas, thusincreasing the internal pressure in the cold finger 30 during thecritical thaw phase before releasing the thawed gas. See also co-pendingand co-assigned U.S. patent application Ser. No. 08/989,604 to Driehuyset al. However, it has been discovered that the “optimal” hold time orwaiting period can vary depending on the quantity of gas accumulated,the flow rate used during accumulation, and the like. Therefore, inorder to increase reliable post-thaw polarization, it is preferred thatthe hyperpolarizer unit 10 is configured to monitor the pressure of thegas in the (downstream) plumbing associated with the cold finger 30 andthen to release the thawed gas at a predetermined pressure rather thanat a preset time. In addition, it is preferred that the hyperpolarizerunit 10 is configured to minimize the dead volumes in the plumbingbetween valve 37 and valve 52 as well as the pressure transducer deadvolume (52-54).

In operation, the thaw method is performed with cold finger valve 37open, the valve 47 still closed, the valve 52 open, and the valves 55and 58 still closed. This configuration adds a small dead volume ofabout 7.3 cc's to the cold finger 30, the internal volume of which istypically about 22 cc's. Thus, the thaw speed itself is generally notadversely affected by the configuration change, but the pressuremonitoring now provided allows a more predictable and repeatable openingof the valve associated with the control of the gas exiting the coldfinger 30 (now valve 47). That is, during thaw, a major portion of thehyperpolarized gas transitions directly from a frozen solid into aliquid phase corresponding to the pressure in the cold finger during thethawing step. Preferably, the predetermined release pressure is set atabout at least 1 atmosphere. Opening the valve after the pressurereaches 1 atm has shown improved xenon post thaw release for 100-600cc's of accumulated ¹²⁹Xe. Interestingly, lowering the release pressure(such as to 0.8 atm) can introduce unreliable post-thaw polarizationlevels and slow the rate at which the polarized gas exits the coldfinger.

Although polarized thawed ¹²⁹Xe is directed into the dead volume in apost-thaw path (the path downstream of valve 47 and between valves52-55-58) and may depolarize therein, the rapid release of the thawedpolarized gas once valve 47 is opened is such that little of thedepolarized gas enters into the exit path 114, 114 a (i.e., once valve47 opens, substantially all of the thawed gas flows into the pathdefined between valves 37-47-50). In any event, even if depolarized gasin the dead volumes mix with the primary polarized thaw gas, it is arelatively small volume compared to the typical collection volumes thatthe overall polarization is minimally reduced. Preferably, as will beappreciated by those of skill in the art, other pressure monitoringsensors and plumbing configurations can also be employed, in which thepressure monitor and plumbing are configured to minimize the dead volumeexperienced by the hyperpolarized gas during the thaw phase of theprocess.

In any event, as the hyperpolarized gas flows in the exit line 114, thegas exit flow path includes both a primary flow path 114 a which directsthe gas toward the filling point 50, and a secondary flow path along thebleed line 115. As such, a small amount of the hyperpolarized gas isdiverted away from the primary flow path 114 into the secondary flowpath formed by the bleed line 115 and the secondary reservoir 120.Preferably, the secondary reservoir 120 is sized and configured suchthat it has a minimal volume, i.e., a quantity sufficient to determine areliable polarization level which does not substantially deplete theuseable volume of hyperpolarized gas. In one preferred embodiment, thesecondary reservoir 120 has an internal free space volume of about 2 cc.Similarly, the bleed line 115 is configured and sized to have a minimalvolume along its length such as ¼ inch outer diameter tubing typicallyhaving about a 3-4 cc. inner volume along its length. As such, in apreferred embodiment, the secondary flow path polarization measurementuses only about 6 cc. of gas, a relatively insubstantial volume comparedto the typical 1 liter volume of gas collected at the exit 50.

In a preferred embodiment, as shown in FIG. 1, a dual symmetry NMR coil100 is positioned such that one surface contacts the polarizer cell 22while the other contacts the secondary reservoir 120. A magnetic fieldoperably associated with the optical cell 22 (typically provided by apair of Helmholtz coils such as those schematically shown in FIG. 9 atelement 500) has a region of homogeneity defined thereby. Preferably,the region of homogeneity envelops a major portion of the polarizer cell22, the NMR coil 100, and at least a top portion of the secondaryreservoir 120 a, i.e., the portion of the secondary reservoir 120adjacent the NMR coil 100. A typical region of homogeneity isschematically illustrated by the dotted line box designated B₀ in FIG.1. Preferably, the homogeneity is sufficient in the measurement regionto allow a reliable reading of the hyperpolarized gas, as magnetic fieldgradients can act to depolarize the diverted gas (i.e., thehyperpolarized gas in the secondary reservoir 120), potentiallyintroducing inaccurate measurement representation of the post-thawpolarization.

Preferably, for effective polarimetry measurements, it is preferred thatthe T₂* value be in excess of about 5 ms (the typical mute time afterthe pulse is transmitted is about 3 ms). This means that for ahyperpolarizer unit 10 with a magnetic field generated by “on-board” 19inch diameter Helmholtz coils 500, the coils are positioned andconfigured to generate a region of homogeneity which is defined by avirtual cylinder having a length of about 2 inches and a radius of about2 inches centered between the coils 500. The polarizer or optical cell22, an example of which is shown in FIG. 9, thus has a correspondingconfiguration and volume which is designed to substantially fit withinthe region of homogeneity. In addition, the magnet means is configuredto extend the region of homogeneity such that it is sufficient toinclude the dimensions of the dual symmetry coil 100 and at least theclosed end of the secondary reservoir 120. For example, a polarizer cell22 with a radius of about 0.75 inches, a NMR dual symmetry monitoringcoil 100 of about 0.375 inches, and the secondary reservoir 120 of about0.5 inches would be suitable (1.625 inches).

In one embodiment, as shown in FIG. 6, the center of the magnetic fieldgenerated by the Helmholtz coils 500 is shifted to be offset relative tothe center of the optical cell 22. This offset is schematically shown bya first magnetic field central axis along the line A—A to a second axisshifted closer to the NMR coil 100 indicated by the axis line A′—A′. Theoffset can facilitate the configuration of the magnetic field issufficiently homogeneous in the region associated with the NMR coil 100and/or the NMR coil 150 for more sensitive monitoring of thepolarization of the gas thereat.

Of course, the secondary reservoir 120 and associated NMR coil andoperating circuitry (together a NMR coil and related pulse measurementoperating circuitry, when positioned after the polarizer cell 22 can bedescribed as a “post-optical cell monitoring system”) can operate fornon-cryogenic accumulation systems as well. For example, subsequent tothe optical pumping of the gas, such as during fill, a small portion ofa hyperpolarized gas can be directed away from the gas flow path intothe secondary reservoir 120 to indicate the degree of polarization atthe filling point in the production cycle (such as when filling ³He viaa fill port (not shown) into a portable container). Alternately, asecondary flow path can be provided at other critical or desiredmonitoring points in the production cycle.

In a preferred embodiment, as shown in FIG. 8, the secondary reservoir120 is positioned adjacent the dual symmetry NMR coil 100 which ispositioned adjacent the polarizer cell 22 in the oven 122 such that itcan monitor the polarization of the hyperpolarized gas both in the cell22 and in a secondary reservoir (or post-thaw bulb) 120. That is, theNMR coil 100 is sandwiched between the polarizer cell 22 on one side andthe secondary reservoir 120 on the other. As such, the secondaryreservoir 120 is preferably positioned in the oven 122 alongside thebottom of the optical cell 22. The NMR coil lead 111 (such as lead 106shown in FIG. 2B) are configured to exit the bottom of the oven 122 andthen electrically connect with a detection circuit circuit 100D (FIG.5). In operation, when activating the secondary reservoir 120, it ispreferred that the oven temperature be known and controlled because athigh temperatures the gas density of xenon will be reduced according tothe relationship expressed by the ideal gas law (PV=nRT). For example,if the oven 122 is set at 150° C., the density of xenon in the secondaryreservoir 120 is about (295K/423K or 0.70) of the room temperaturedensity. The signal associated with the hyperpolarized gas in thesecondary reservoir 120 is reduced correspondingly. Therefore, thesignal data can be corrected for known oven 122 temperature values toreflect a representative room temperature reading.

FIGS. 2A and 2B illustrate a preferred embodiment of a dual symmetry NMRcoil 100. In a preferred embodiment, as shown in FIG. 2A, the body ofthe NMR coil 100 includes opposing first and second flange portions 101,102 and a center coil-receiving portion 105 a. The body is preferablyformed of a non-conducting material such as FLUOROSINT 500. Conductingcoil 105 is wrapped onto the center coil-receiving portion 105 a of thecoil body. Preferably, about 350 turns of 30 AWG (copper) wire iswrapped along the center coil-receiving portion 105 a. The conductingcoil 105 wire turns can be secured onto the NMR coil body centercoil-receiving portion 105 a such as with ¼ inch glass tape. It is alsopreferred that the wire forming the conducting coil 105 be selected tohave about a 200° C. continuous service rating. This will allow thewinding to withstand the operating temperatures inside the oven 122(typically about 160-200° C.). As shown in FIG. 2B, the NMR coil 100also includes a length of wire 106 extending from the coil 100 toconnect it to a NMR polarization detection circuit 100D (FIG. 5). Afirst major portion of this wire length 106 is preferably formed as aset leads having a major twisted portion 106A having a twistconfiguration of about 8 twists per inch and extending with anassociated length of about 16 inches. As is also shown in FIG. 2B, aminor portion 106B of the two leads 106 is untwisted. Preferably theminor portion is about two inches in length (less than about 20% of thetwisted length). In a preferred embodiment, the untwisted portion 106Bof the leads 106 are stripped and plated with a conductive metal platingsuch as tin. The NMR coil 100 is preferably configured such that thecoil spool center receiving portion 105 a has about a 0.5 inch (1.27 cm)diameter with the coil layers winding out the coil 105 to about a 0.85inch (and typically under 1.0 inches) diameter. In a preferredembodiment, the NMR coil 100 is configured to provide a DC resistance ofabout 7.0±1.0Ω and an inductance of about 2.13±0.2 mH. Typically, theNMR coil 100 is tuned to resonate at about 25 kHz which corresponds to afixed capacitor of about 20,000 pF. This yields a Q value of about 20.

The first and second flange portions 101, 102 have “dual symmetry” withrespect to the center coil portion 105 a (i.e., they are sized andconfigured the same). Advantageously, the dual symmetry configuration ofthe NMR coil 100 allows the same NMR coil 100 and the same NMRpolarization detection circuit 100D to be used to measure thepolarization of the gas at two different points in the production cycle,i.e., at two different locations in the hyperpolarizer unit 10; at thepolarizer cell 22 and at the secondary reservoir 120 associated with thegas proximate to the dispensing outlet 50. As such, in operation, in apreferred embodiment, an upper exposed planar perimeter surface 100 a ofthe first flange portion 101 is positioned to contact the optical celland the lower exposed perimeter surface 100 b of the second flangeportion 102 is positioned to contact the secondary reservoir 120.

In a preferred embodiment, the two flange portions 101, 102 have arelatively small or thin width of less than about 0.1 inches (2.54 mm),and more preferably of less than about 0.063 inches (1.6 mm). This smallor thin symmetrical flange portion configuration can allow the coilconductive portion 105 to be positioned closer to the hyperpolarized gason both flange sides 101, 102 of the NMR coil 100. The NMR coil 100 isabout 0.250 inches in height (about 0.63 cm). As shown, the NMR coil 100also includes a center aperture 103 formed therethrough. Alternatively,the aperture 103 can be filled or the body formed as a solidnon-conductive material in this volume.

FIG. 3 illustrates a preferred embodiment of a secondary reservoir 120(also descriptively called a post-thaw bulb for cryogenic accumulatorapplications). As shown, the secondary reservoir 120 includes anenclosed end portion 121 which is configured to capture thehyperpolarized gas therein. In position on the hyperpolarizer unit 10,as shown in FIG. 1, the enclosed end portion 121 is positioned to facethe adjacently contacting surface of the NMR coil 101 b. The enclosedend 121 is preferably configured with a thin wall face portion, i.e.,the portion which is configured to contact the NMR coil 100. Preferably,the enclosed end 121 is formed of PYREX which is about 1-2 mm thick. Ofcourse, the gas contacting surfaces of the secondary reservoir 120(and/or associated lines or plumbing) can be coated withsurface-relaxation resistant materials or formed from differentmaterials (such as high purity polymers as described in U.S. patentapplication Ser. No. 09/126,448 to Deaton et al.) to increase T₁. Metalfilm surfaces may also be used but care should be taken that they beconfigured sufficiently thin to preclude signal degradation/strength.

FIG. 3 illustrates the enclosed end portion 121 as a substantiallyplanar face and is preferably configured to rest against the bottom ofthe NMR coil 100. However, it will be appreciated by one of skill in theart that the present invention is not limited thereto. For example, FIG.3A illustrates an alternative configuration for the secondary reservoir120′ which configures the enclosed end 121P with a circumferentiallypositioned upstanding ridge 121P. This ridge is configured and sized toreceive the outer diameter of the bottom flange of the NMR coil 100therein. This configuration can provide easy alignment with the coil100. Precise aligmnent and reliably repeatable positioning of the NMRcoil 100 can improve the accuracy and reproducibility of the calibrationacross multiple hyperpolarizers during increased production builds andcan also facilitate a more repeatable replacement of the coil in thefield.

The secondary reservoir 120 also includes a second end 122 which isconfigured to attach to the plumbing of the hyperpolarizer unit 10 alongthe bleed path 115. The secondary reservoir 120 also includes alongitudinally extending central portion. The secondary reservoir 120includes a passage 124 which defines a free volume of about 3-4 cubiccentimeters and which is open to allow gas to flow through to theenclosed end 121 thereof. As the bleed line 115 and the secondaryreservoir 120 have hyperpolarized gas contacting surfaces, it ispreferred that they be configured to minimize contact induceddepolarization, i.e., the walls and valves, O-rings and the like areformed of polarization friendly materials or coatings. See U.S. Pat. No.5,612,103 to Driehuys et. al.; see also co-pending and co-assignedpatent application Ser. No. 09/126,448. The disclosures of which arehereby incorporated by reference as if recited in full herein. In apreferred embodiment, the secondary reservoir 120 is configured with abody which has a surface induced contact relaxation which is longer thanabout 10 seconds, more preferably longer than about 30 seconds, and mostpreferably longer than about 2.0 minutes, to allow sufficient time tocollect a NMR signal and obtain a polarization reading.

FIG. 4 illustrates a perspective view of a plumbing diagram for apreferred embodiment of a hyperpolarizer unit 10 according to thepresent invention. As shown, the NMR coil 100 is positioned adjacent alaterally intermediate bottom portion of the polarizer cell 22 (but can,of course, be alternatively positioned as long as it is within asuitably homogeneous magnetic field). The NMR coil 100 is positionedintermediate the polarizer cell 22 on one end and the secondaryreservoir cell 120 on the other.

FIG. 5 illustrates an electrical block diagram layout for a preferredon-board polarization monitoring embodiment for the NMR coil 100 of thepresent invention. As shown, a single unitary NMR detection circuit 100Dcan be employed to monitor the polarization level of the gas via the NMRcoil 100 during the production cycle, namely, the polarization level atthe optical (polarizer) cell 22P and the polarization level of thepolarized gas at the secondary reservoir 120P. This configuration allowsthe same NMR coil, the same circuit and cables to monitor two gaslocations. This dedicated circuit 100D can eliminate the switching ofcables and pulse parameter adjustments needed for operation. Foradditional NMR coils positioned in alternate locations along theproduction path, such as in a post-accumulation region, a pre-dispensingregion, or at a position along the exit flow path 113P in thehyperpolarizer unit 10, one can physically or electrically switch cablesor other operational circuitry to look at the desired position (shownfor example in FIG. 14 as 302S). For example, in the case of the solid¹²⁹Xe (frozen), a different NMR circuit may be used to drive a higherfrequency excitation pulse as will be discussed further below.

Conventionally, as shown in the bottom graph of FIG. 13, NMR usesheterodyning or homodyning techniques to mix the received signal with acarrier of similar frequency. In operation, these techniques give a sumand difference frequency as will be appreciated by those of skill in theart. However, unless a quadrature (2 channel) detection scheme is usedand the signal is Fourier Transformed (FT) before analysis, inaccuratesignal measurements can result, especially at low differencefrequencies. Low difference frequencies are typically necessary to staywithin the bandwidth of the coil response and to pulse the nulcei neartheir resonant frequency. This can be problematic when attempting toanalyze the signal and calculate the polarization.

FIG. 14 illustrates a suitable prior art NMR detection circuit 100Dwhich has been modified to add a circuit switching means 302S. Generallydescribed, the NMR detection circuit 100D uses a low field spectrometeror transmitter 302T which comprises a power supply 310, a pulsegenerator 300, and a transmit amplifier 302. A transmit/receive line(111) connects the coil 100 to both the transmitter 302T and a receiver305R. The receiver 305R shown includes a receive amplifier 305 andcomputer 309 and can also include a filter 307. As is also shown, theNMR detection circuit 100D also preferably includes diode gates 209 todirect the signal from the transmitter to the coil 100 or from the coil100 to the receiver portion of the circuit 100D according to theoperational mode of the NMR detection circuit. In one embodiment, thecircuit 100D can employ a simple receiver analyzer which includes apeak-to-peak detector which translates the peak detection into apolarization level and a simple display or oscilloscope output (it doesnot require a computer to evaluate or measure the polarization).

Preferably, the NMR detection circuit 100D is configured to avoid theneed to mix the received signal. Instead, the received signal isamplified, filtered, and analyzed via FID (free induction decay),directly. This direct FID analysis allows a non-complex single channelsignal detection and advantageously reduces the complexity of the signalanalysis circuitry (no complicated FT's). FIG. 13 shows a graphiccomparison of a direct detection method with a typical mixed-down (twochannel FID). The original FID frequency is 75.1 kHz and the associatedT₂* is 5.16 ms. The mixed-down FID frequency is 200 Hz. Both channels ofthe mixed-down FID underestimate the peak-to-peak amplitude of thesignal. Further detuning can provide more oscillations but signalstrength can be reduced because the exictation pulse is applied fartherfrom the resonance of the spins. The direct-detect FID method allowsoperation directly on the resonance of the NMR coil and the spins. Manyof the oscillations occur before de-phasing so that a more accuratemeasurement of peak-to-peak amplitude can be made.

The polarization is proportional to the peak-to-peak amplitude of theFID, which can be analyzed using cursors or relatively inexpensive peakdetection circuitry. In this preferred method, numerous cycles occur inthe direct-detect mode before attenuation due to T₂* sets in.Accordingly, this direct-detect method is more accurate overconventional mixed down FID measurements. Further, because of theelimination of the requirement for homodyning, one can operate directlyon the coil response resonance which also allows for improved accuracy.Of course, other polarimetry configurations can be used as is known tothose of skill in the art. See e.g., Saam et al., Low Frequency NMRPolarimeter for Hyperpolarized Gases, Jnl. of Mag. Res., 134, pp. 67-71(1998).

As shown in FIG. 14, it is preferred that the NMR detection circuit 100Demploy a hot carrier Shotky diode gate 209 which have a 0.25V conductionvoltage. This type of diode gate can reduce distortion (standard diodegates in NMR are 1N914A diodes with conduction voltages of about 0.6V).This can also reduce the ring-down time of a NMR coil after excitationto about 0.2 ms, thereby allowing the FID to be sampled about 3.5 msearlier than other monitoring systems for hyperpolarizer units. It isalso to be noted that the using a diode gate can introduce signalleakage problems. The diode gate 209 includes two diodes connected inparallel with opposite polarities. In operation, one of the diodes isalways in conduction (assuming the voltage is above the diode drop)irrespective of the sign of the voltage. If the voltage is below thediode drop, then both diodes act to block and prevent any signal frompassing (i.e., act as a gatekeeper). As shown in FIG. 14, the diodegates 209 act to send small signals from the coil 100 (a signal with avoltage which is below the diode voltage drop) to the receiver 305Rrather than back into the transmitter 302T. However, during transmittalof the pulse (at voltages much larger than the diode voltage drop), thediode gates 209 act like a conductor to the coil 100.

As also shown in FIG. 14, the NMR detection circuit 100D preferablyemploys a single fixed capacitor 230 for tuning a corresponding NMR coilcircuit 200. NMR coil circuits 200 are typically “tuned” by putting acapacitor “C” in parallel with the excitation coil (which has anassociated inductance “L”). The coil circuit resonates at a frequency“f” and therefore can enhance response to signals at or near thatfrequency, while also having reduced response to noise outside of itsfrequency bandwidth. In typical NMR circuits, a series/parallelcombination of adjustable capacitors are used to tune the circuit toresonance and to have an impedance of 50 Ohms (typically required forhigh-frequency operation). This type of capacitor configuration canrequire frequent and careful adjustments to same to ensure a properlytuned circuit. Thus, it is preferred that a single, high-precision,fixed-value capacitor be used in the NMR detection circuit 100D to tunethe NMR coils described herein. This is accomplished by also using thediode gate 209 and low operating frequencies (about 1-400 kHz) in theNMR detection circuit 100D.

Flow Path Monitoring Coil

FIG. 6 illustrates an alternate hyperpolarizer unit 10 with two separateNMR coils 100, 150. As shown in FIG. 7A, the second NMR coil 150 isadvantageously positioned along the post-polarizer or optical cell flowpath 122 or adjacent the cell exit port 22 b. This positioning canprovide a more reliable level of polarization of the gas as it actuallyexits the cell 22, rather than the level conventionally monitored by NMRcoil's typically mounted beneath the center portion of the optical cell.Although the conventional configuration can give good readings absentflow, during flow, the gas passing over the coil is typically not fullypolarized compared to the level it should obtain as it ultimately flowsout of the exit port of the optical cell. Thus, the position of a NMRcoil 150 adjacent the polarizer cell outlet 22 b can give a NMR signallevel commensurate with the flow of the gas as it exits the polarizercell 22, and, as such, can provide an improved production controlmeasurement parameter for the polarization level of the gas achieved atthis process flow point. Although shown in a preferred embodiment with axenon substantially continuous flow optical cell 22, this flow pathmonitoring can, of course, also be used with batch mode hyperpolarizers(typically used to produce hyperpolarized ³He). This can allow aconvenient NMR coil measurement prior to dispensing but in the gas exitflow path adjacent the polarizer cell 22.

FIG. 7B illustrates a fabrication technique for including such amonitoring coil 150 on the cell exit leg 22 b adjacent the major cellbody. As will be appreciated by one of skill in the art, the polarizercell 22 is typically formed by a skilled molten glass-forming artisan.Thus, typically, the glass body is formed and then the legs are formedtherein to form the optical cell 22. In order to position a NMR coil 150along the glass body 119B adjacent the exit port 22, the conventionalfabrication process can be altered as shown in FIG. 7B. In this method,the glass body 119B is formed and an upper portion of the leg 119L (theupper and lower portions 119L1, 119L2 defining the exit leg 122) isformed (blown). Next, the NMR coil 150 is slipped over the partiallyformed leg 119L1 and positioned to extend above the lower portion of theleg 119L2 which includes the expanded section and plumbing attachments28 to provide the optical cell NMR monitoring coil 150 as shown in FIG.7A. Alternatively, the NMR coil 150 can be attached to a cell body at anexit aperture region and a single integral leg 122 can be attached ordrawn therethrough (not shown).

The NMR monitoring coil 150 is preferably configured with a centeraperture which is sized to be slightly larger than the outer diameter ofthe leg 221 so that the NMR coil 150 can be slid over the leg andpositioned adjacent the primary body of the optical cell, while alsobeing sized and configured to be held securely thereagainst. The glassbody 119B and legs 119L1, 119L2 can be formed from PYREX®.Alternatively, the body and legs can be formed of materials which aresubstantially non-paramagnetic and non-conducting such asaluminosilicates and the like.

In operation, it is preferred that for NMR coils 150 positioned alongthe exit flow path arm of the cell 22, the flow of the hyperpolarizedgas is temporally stopped or slowed while the polarization measurementsignal is obtained in the NMR coil 150 to maintain a sufficient quantityof the polarized gas proximate to the NMR coil 150 while the FID signalis obtained. For example, xenon gas is passed at a desired flow ratethrough the polarizer cell 22 and out of the exit port 22 b. The valvescan be temporarily closed to cease the flow of the polarized gas out ofthe exit port 22 b, receive the NMR signal via the NMR coil on theoutlet arm 150, and re-start the flow of the polarized gas. This flowinterruption time cycle is preferably short, such as under 10 seconds.Of course, a bleed line (not shown) can also be positioned in fluidcommunication with the exit port 22 b and used to direct a smallquantity of the polarized gas to an in-process measurement NMR coil(such as the dual symmetry NMR coil or another separate NMR coil (notshown)) in a homogeneous field region of the hyperpolarizer for ain-process flow reading, thus not requiring the flow to be suspended fora reliable flow path measurement. Alternatively, the NMR coil 150 canabut the cell itself and be configured and sized about the cell toprovide reliable information about the polarization of the gas as itapproaches the cell exit. Of course, other flow path NMR coilconfigurations can also be used such as other plumbing or valveconfigurations to direct and capture a sufficient quantity of gas in theflow path to measure the polarization of the gas in the flow path.Advantageously, signal information representative of the polarization ofthe flowing gas can allow for more precise process parameter adjustment(such as in the operation of the optical cell) and real-time processinformation.

Although FIG. 6 illustrates the hyperpolarizer 10′ with both the NMRmonitoring coil 150 and the dual symmetry coil 100, the presentinvention is not limited thereto. For example, the hyperpolarizer 10′can be alternatively configured with just the outlet arm NMR monitoringcoil 150, and/or with the NMR monitoring coil 150 spatially translatedto be mounted at a different position along the optical cell exit leg.

Cryogenic Monitoring

FIG. 8 illustrates yet another embodiment of a hyperpolarizer unit 10″according to the present invention. In this embodiment, thehyperpolarizer unit 10″ includes a cryogenic NMR monitoring coil 175. Asshown, this monitoring coil 175 is preferably positioned in thehyperpolarizer unit 10″ to monitor the polarization of the collected,i.e., frozen (iced) polarized gas. Because this monitoring coil 175 canbe exposed to extreme conditions (cryogenic temperatures), it ispreferred that the NMR monitoring coil 175 be formed of body and wirematerials which are suitable for same. One example of a suitable wire isa thermoplastic coated copper wire, other suitable materials includeUltem®, Nylatron®, or Torlon® polymers and the like. Of course, theresistance of the wires at the lower temperatures will be reduced andthe NMR detection circuit 100D″ is preferably configured to account fortemperature-induced variance. The lower resistivity of the wire mayimprove the “Q” of this circuit, but, as will be appreciated by those ofskill in the art, the lower resistivity is typically insubstantial whencompared to inter-wire capacitance in low-field applications (whichdominates the “Q” of the circuit). That is, the NMR coils of the presentinvention employ numerous windings (typically 100-300) compared to a fewturns of wire on a coil for typical high-field applications (where the“Q” can be dominated by wire resistivity).

The cryogenic NMR monitoring coil 175 can be configured in several ways.In one preferred embodiment, as shown in FIG. 9, the NMR coil 175 isconfigured as a solenoid which is positioned around the collectionchamber of the cold finger 30. As shown in FIG. 9A, the NMR coil 175 isconfigured as a solenoid 175 a (in contrast to the surface coil type 175b shown in FIG. 10) to wrap around a lower portion of the exterior ofthe cold finger 30 or collection chamber itself. Preferably, thesolenoid 175 a can be configured and sized to extend and proximate tothe exterior of the cold finger such that it is proximate tosubstantially the entire ice reservoir or holding region of thecollection chamber (i.e., the region where the frozen gas ispositioned).

As is well known to those of skill in the art, for the NMR measurementto operate properly, the magnetic field source is preferably configuredto generate a magnetic field which is transversely oriented(perpendicular or normal) to the direction of the field associated withthe pulsing of the corresponding NMR coil. Therefore, the magnetic fieldsource operably associated with the cryogenic NMR coil 175 (whetherpermanent magnets 40 or electromagnets 40′) is configured to generatethe appropriately directed magnetic field as well as a sufficient degreeof homogeneity for the NMR measurement.

FIG. 9 illustrates the magnetic field source for the cryogenic NMR coil175 as a set of permanent magnets 40. However, the magnetic field sourcecan also be configured as an electromagnet or solenoid 400 andpositioned to be spatially separated with the cold finger 30intermediate thereof about the lower region of the cold finger whichholds the frozen gas. In operation, the magnitude of the magnetic fieldsource (shown for example as a permanent magnet 40 in FIG. 9 and anelectro-magnet 400 in FIG. 11) is preferably configured to generate asubstantially fixed or constant low-level magnetic field of at leastabout 500 G so that the resonant frequency of ¹²⁹Xe is about 589 kHz.Allowing about 300 pF of capacitance in the signal measuring/detectioncircuit to resonate the collected frozen gas, it is preferred that theNMR coil 175 a is configured with an inductance of about 0.24 mH orless. In addition, because the magnetic field is substantially fixed, itis preferred that the measurement or detection circuit is tunable withsome amount of variable capacitance to adjust the tuning to match theLarmor frequency of the frozen ¹²⁹Xe. In a preferred embodiment, thecryogen based NMR coil 175 a and associated detection circuit isconfigured with a capacitance which includes a tunable amount of about0-100 pf, and about 100 pf due to cabling or wiring, and about a 100 pFfixed capacitor. Preferably, the NMR coil 175 a is sized such that itcovers (extends about) the entire ¹²⁹Xe ice collection region. Forexample, a NMR coil 175 a with a winding length of about 2 cm and aradius of about 1 cm may be suitable. In this example, about 220 turnsof wire will provide about 0.24 mH inductance.

In operation, the applied static magnetic field (B₀) is oriented to beperpendicular or normal to the NMR coil RF field (B₁) provided by theNMR coil. Thus, if B₀ is transverse, then B₁ is axial, or if B₀ isaxial, then B₁ is transverse. For clarity, the axial direction means thedirection which is parallel to or collinear with the upright cold finger30 (shown in position in FIGS. 10 and 11).

In a preferred embodiment, to generate a transverse magnetic field B₀, apair of opposing ceramic magnets are used as described above and thecorresponding B₁ is thus axial and applied via a NMR coil 175 aconfigured as a solenoid. However, as is known to those of skill in theart, an electromagnet coil 40′ (such as a Helmholtz pair) can also beconfigured to generate a transverse static magnetic field B₀. Anotheralternative is to use a transversely oriented solenoid for the staticfield with an axially oriented B₁ associated with the NMR coil 175 a asschematically shown in FIG. 11. Electro-magnet configurations whichprovide suitable axial fields include a relatively large solenoid for anaxial B₀ (such as 20-30 cm long and 10 cm in diameter) and a smallsolenoid associated with the B₁ of the NMR coil (such as 2 cm long and 2cm in diameter).

In conventional cryogenic accumulators, the typical magnetic fieldstrength surrounding the frozen accumulated polarized gas is provided bya permanent magnet arrangement generating a relatively low field and notparticularly homogeneous magnetic field. The homogeneity generatedthereby is suitable for frozen gas which is not particularly susceptibleto magnetic gradients, but unfortunately the permanent magnetarrangement used in the past is generally not homogeneous enough forsensitive and/or precision NMR measurement. See e.g., U.S. Pat. No.5,809,801 to Cates et al. and U.S. patent application Ser. No.08/989,604 to Driehuys et al. for more details of the cryogen permanentmagnet yoke.

Therefore, in a preferred embodiment as shown in FIG. 10, when apermanent magnet arrangement is employed with the cryogenic NMR coilmonitor 175, it is preferred that the permanent magnet arrangement 40′be modified to fit outside the cryogen bath 43. Preferably, thepermanent magnet arrangement 40′ is sized and configured to produce amagnetic field of from 1-2000 Gauss, more preferably about 50-1000Gauss, and still more preferably about 500-1000 Gauss. It is alsopreferred that the magnet field have a homogeneous region sufficient toextend across the lower portion of the cryogenic compartment.Preferably, the homogeneity is sufficiently high so that gradientinduced T₂* is longer than the T₂ of the ice. For example, longer thanabout 1 ms, which is the intrinsic T₂ associated with solid ¹²⁹Xe at77K. See Yen et al., Nuclear Magnetic Resonance of 129Xe in Solid andLiquid Xenon, Phys. Rev. 131, 269-275 (1963).

Preferably, in order to obtain sufficient homogeneity, the permanentmagnet arrangement 40 is configured with a physically larger magnetassembly relative to that used for the cryogen cold finger accumulationin the past. For example, one configuration is to employ about 20 cmdiameter magnets (disks) with magnet poles which are separated acrossthe dewar or liquid cryogen bath container by a separation distance ofabout 8 cm which can provide about a 500 Gauss field with sufficienthomogeneity about the desired region. Stated differently, a set ofdiscrete permanent magnets 40 are positioned opposing the other acrossthe outer wall of the dewar flask or cryogen bath container 43 such thatthe diametrically opposed permanent magnets 40 have a diametricseparation of about 8 cm (3 in). Alternatively, the permanent magnets 40can be a series of stronger field ceramic magnets (the latter canincrease the field strength generated by same).

As shown in FIG. 10, the permanent field disk magnets 40 can be alignedby a structural yoke 401 and/or can include a flux return. As will beappreciated by one of skill in the art, a flux return can increase thefield strength of this arrangement while also minimizing interferencefrom stray magnetic flux. The flux return can be configured as a softiron material. Alternatively, in lieu of a yoke 401, the magnets 40 canthemselves be secured to the outside wall of the cryogen container orflask 42 holding the cryogen bath 42 or otherwise supported to providethe desired spatial separation and alignment. Of course, as will beappreciated by those of skill in the art, other magnet geometryconfigurations can be used to provide a suitable magnetic field strengthand homogeneity.

FIG. 10 also illustrates an accumulator and magnet assembly 230. Theaccumulator 30 is supported by a support platform 210 positioned overthe cryogen bath 43. The magnets are separated a distance “D” andpositioned external to the cyrogen bath 43. As discussed above, theseparation distance “D” is at least about 8 cm for a magnet disk havingabout a 20 cm diameter. A pair of plates 215 longitudinally extend fromthe support platform 210 and connect to the bottom of the holdingassembly 275 which is sized to hold the NMR coil 175 b to contact thebottom of the collection reservoir 75 of the accumulator 30 to providethe desired magnetic field to the collected polarized gas. As shown, theaccumulator 30 includes a support contact portion 211, which isconfigured to rest against the support platform 210 and has a lateralsupport member 215 a which extends to hold the top portion of thecollection reservoir 75. In any event, the accumulator 30 is preferablyimmersed in the cryogen bath 43 such that the reservoir 75 and about 3-6inches of the tube are immersed. If submerged in liquid nitrogen, theexterior wall of the outer sleeve 103 and the exterior wall or thereservoir 75 will be at about 77° K. The freezing point of xenon isapproximately 160° K. Thus, upon exiting the primary flow path 80, thehyperpolarized gas hits the cold surface and freezes into the reservoir75 while the buffer gases exit the accumulator via an exit channel 90(not shown). The reservoir 75 can include a surface coating to helpprevent relaxation caused by the polarized gas's contact with same. FIG.11 illustrates the NMR coil 175 c alternatively configured andpositioned as a solenoid type excitation coil which extends about thelength “L” of the accumulation bulb or reservoir 75 and is preferablyconfigured to contact or extend in close proximity to the exterior ofsame (a cryogen immersed portion) of the reservoir 75.

FIG. 9 illustrates a hyperpolarizer unit 10′″ with a multi-pointpolarization monitoring system. This embodiment includes the first NMRcoil 100 positioned adjacent the optical cell 22 and secondary reservoir120, the second NMR monitoring coil 150 positioned adjacent the opticalcell exit 22, and the third cryogenic NMR monitoring coil 175 positionedto monitor the polarization of the frozen gas. FIG. 9 also illustratesan evacuated bag or vessel 525 attached to the dispensing outlet 50 andthe secondary flow path 115 in fluid communication with the exiting gasflow path proximate the gas dispensing port 50. FIG. 12 schematicallyillustrates a hyperpolarizer detection circuit for a multi-NMR coilmonitoring system.

Although particularly suited for cryogenically accumulated ¹²⁹Xe, theinstant multi- or dual-polarization monitoring method can alsosuccessfully be employed on a hyperpolarizer used with otherhyperpolarized noble gases such as ³He.

Preferably, the NMR coils 100, 125, 175 of the instant invention arehigh precision NMR coils. That is, it is preferred that the NMR coilsare designed and produced in a reliable and substantially consistentmanner (such as to controlled tolerance and controlled manufacturingprocesses, preferably to six sigma production standards). This allowsthe hyperpolarizer to establish a calibration standard which issubstantially the same for a particular position on the hyperpolarizeracross replacement modules.

Operation

A “T₁” decay constant associated with the hyperpolarized gas'longitudinal relaxation time is often used to describe the length oftime it takes a gas sample to depolarize in a given situation. As notedabove, the handling of the hyperpolarized gas is critical because of thesensitivity of the hyperpolarized state to environmental and handlingfactors and the potential for undesirable decay of the gas from itshyperpolarized state prior to the planned end use, i.e., delivery to apatient for imaging. Processing, transporting, and storing thehyperpolarized gases—as well as delivering the gas to the patient or enduser—can expose the hyperpolarized gases to various relaxationmechanisms such as magnetic gradients, contact-induced relaxation,hyperpolarized gas atom interactions with other nuclei, paramagneticimpurities, and the like.

Referring now to FIG. 14, generally described, a selected RF excitationpulse (of predetermined frequency, amplitude, and duration) istransmitted from a pulse generator 300 via an amplifier 302 through aset of diode gates 209 to the surface coil 100. The transmittedexcitation pulse locally excites the hyperpolarized gas (or frozen gas)sample 250. The circuit 100D may include a switching means 302S(electrical, mechanical, or program/software directed switches) toswitch between the differently located detection coils in the productioncycle. Alternatively or in addition to the switching means 302S, forhigh-frequency ice measurements an alternate transmitter 302T circuitmay be employed. Of course, an alternate receiver circuit or additionalcomponents associated therewith can also be employed (not shown).

The hyperpolarized gas 250 responds to the excitation pulse inducing aresponse signal back to the receiver 305R through an amplifier 305(optionally filtered) and then to the a computer driven interrogationsignal analyzer 309. Thus, a response signal is received correspondingto the response of the gas to the excitation pulse. The received signalis analyzed (preferably peak to peak, direct FID detection) to determinethe polarization of the hyperpolarized gas. Conveniently, the relativelynon-complex analysis does not require a computer or complex signalprocessor, but can instead employ a peak detector analysis circuit.

Preferably, the excitation pulse is a RF pulse having a selected pulsetime and frequency which corresponds to the strength of the magneticfield and the particular hyperpolarized gas. Preferably, frequenciesused for ³He gas phase are about 75 kHz (with a static magnetic field ofabout 23.4 G) or more (with an associated change in the magnetic fieldstrength). An alternative preferred frequency is about 24 kHz with thefrequency for gaseous ¹²⁹Xe also being preferably about 24 kHz (with thefrozen phase frequency being increased, i.e., being a higher frequencythan the gas excitation pulse frequency). Thus, 24 kHz can be used forboth ¹²⁹Xe and ³He. Because ³He has a larger magnetic moment (2.7 times)compared to ¹²⁹Xe, the magnetic field used for ³He is typically smallerat a similar frequency. Thus, for 24 kHz, about a 20 (20.4) G field ispreferably used for ¹²⁹Xe while about a 7 (7.5) G field is used for ³He.The ¹²⁹Xe resonance frequency is proportional to field strength by theknown ratio of 1.18 kHz/G; thus, as noted, for a 20 G field, thefrequency is about 24 kHz while for a 500 G field a suitable frequencyfor gaseous xenon is about 600 kHz. The higher detection frequencypreferably used for the ¹²⁹Xe ice (frozen phase gas) is related to thefact that T₁ is longer at 500 G. Therefore, for a multi-point processmonitoring hyperpolarizer, the NMR detection circuit 100D (FIG. 12) ispreferably configured to transmit a first pulse at a first frequency(f₁) for the NMR coils 100, 125 and a second higher frequency (f₂) forthe ice-positioned NMR coil 175. In any event, the RF pulse generates anoscillating magnetic field which misaligns a small fraction of thehyperpolarized gas (i.e., ³He or ¹²⁹Xe) nuclei from their staticmagnetic field alignment position. The misaligned nuclei startprecessing at their associated Larmour frequency (corresponding to pulsefrequency). The precessing spins induce a voltage in the NMR surfacecoil 100. The voltage is received back (typically amplified) and thesignal is a FID signal. The initial peak-to-peak voltage of this signalis directly proportional to polarization (using a known calibrationconstant). Saam et al. includes more discussion on one way to establishcalibration standards. See Saam et al., supra.

Preferably, each of the NMR coil embodiments 100, 150, 175 describedherein include an input/output line such as single coaxial signal line(handles both the transmit/receive signal) 111 (FIG. 8) which isoperably associated with the transmitter 302T and receiver 302R portionsof the detection circuit 100D (FIG. 14). In operation, the pulsegenerator 309 will preferably be configured to provide an increasedsignal frequency for the ice and operate recognizing that the T₂* of theice will be decreased over that of the gas.

The excitation pulse of the instant invention is selected such that itcan reliably determine the level of polarization while minimallydepolarizing the gas. The optimal pulse voltage depends on severalfactors. Preferably, for the measurement of the ice collectedhyperpolarized gas, the NMR coil 175 a is configured to encompasssubstantially all of the collected frozen (ice phase) hyperpolarized gasin the cold finger 30. In operation, a plurality of pulses withextremely small flip angles are used to excite the frozen gas. As usedherein, “extremely small” means pulse angles of less than about 5degrees, and preferably in the range of about 1-2 degrees. The extremelysmall pulse flip angles minimize the depolarizing effect of the signalmeasurement on the gas/ice. This is attributed to the relationshipbetween the flip angle associated with the excitation pulse and theretained polarization. The signal per pulse flip angle is proportionalto the sine of the pulse angle (theta), while the retained magnetizationis proportional to the cosine of the pulse flip angle (theta). Forexample, for a pulse flip angle of about 2 degrees, the cosine of thetais 0.994. Therefore, even if ten (2) degree flip angle pulses were takenof the sample, this should leave the sample with about 99.3% of theoriginal magnetization and minimally affect the original signal strengthassociated with the unmeasured polarization of the hyperpolarized frozengas. Thus, extremely small flip angles are preferred because one canexpect a substantial signal from the frozen or iced hyperpolarized gasand the signal is relatively strong even with this small flip anglebecause there is both hyperpolarization and the high density of a solid(the solid phase provides about a 1000 time increase over gas phasedensities). At a frequency of about 589 kHz and employing the 220 turncoil 175 a having an inductance of about 0.24 mH as discussed in apreferred embodiment for the NMR coil 175 a (FIG. 9A) above, and using a1V pulse, will yield about 2 degrees of flip angle in the iced sample.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. In the claims, means-plus-function clause are intended tocover the structures described herein as performing the recited functionand not only structural equivalents but also equivalent structures.Therefore, it is to be understood that the foregoing is illustrative ofthe present invention and is not to be construed as limited to thespecific embodiments disclosed, and that modifications to the disclosedembodiments, as well as other embodiments, are intended to be includedwithin the scope of the appended claims. The invention is defined by thefollowing claims, with equivalents of the claims to be included therein.

That which is claimed is:
 1. A method for releasing the post-thawcryogenically accumulated hyperpolarized gas from a cold fingercollection container operably associated with exit flow path plumbing,comprising the steps of: cryogenically accumulating a quantity ofhyperpolarized gas as a frozen sample in a cold finger; monitoring apressure associated with the cryogenically collected hyperpolarized gassample held in the cold finger; thawing at least a portion of thequantity of frozen hyperpolarized gas sample in the cold finger;increasing the pressure in the cold finger, thereby facilitating thephase transition of the hyperpolarized gas from a substantially frozensample into a thawed fluid sample; and releasing the thawed fluidhyperpolarized sample as a gas from the cold finger responsive to whenthe hyperpolarized sample achieves a predetermined pressure based on thepressure determined during said monitoring step.
 2. A method accordingto claim 1, wherein a major portion of said hyperpolarized gastransitions from a frozen solid sample into a liquid phase correspondingto the pressure in said cold finger during said thawing step, whereinthe hyperpolarizer is configured with exit flow path plumbing disposeddownstream of and in fluid communication with the cold finger, andwherein said releasing step is in response to the opening of a valvedownstream of the cold finger in the hyperpolarizer.
 3. A methodaccording to claim 2, wherein said thawing and releasing steps areperformed while the cold finger is held in position on thehyperpolarizer and in fluid communication with the exit flow pathplumbing.
 4. A method according to claim 2, wherein the cold fingerincludes two spaced apart shut off valves associated therewith, at leastone of which is open during the thawing step.
 5. A method according toclaim 1, wherein said hyperpolarized gas sample comprises hyperpolarized¹²⁹Xe.
 6. A method according to claim 1, wherein the hyperpolarizer isconfigured with exit flow path plumbing disposed downstream of and influid communication with the cold finger, and wherein said monitoringstep is carried out by monitoring the pressure downstream of the coldfinger in the exit flow path plumbing.
 7. A method according to claim 6,wherein said exit flow path plumbing comprises a plurality of valves,and wherein said releasing step is carried out in response to theopening of a valve downstream of the cold finger in the exit flow pathplumbing, and wherein the predetermined pressure is at least about 1atm.
 8. A method of releasing post-thaw cryogenically accumulatedhyperpolarized gas from a cold finger collection container associatedwith exit flow path plumbing, comprising the steps of: cryogenicallyaccumulating a quantity of hyperpolarized gas as a frozen sample in acold finger; monitoring a pressure associated with the cryogenicallycollected hyperpolarized gas sample held in the cold finger; thawing atleast a portion of the quantity of frozen hyperpolarized gas sample inthe cold finger; increasing the pressure in the cold finger tofacilitate the phase transition of the hyperpolarized gas from asubstantially frozen sample into a thawed sample; storing the thawedsample in fluid connection with the cold finger; measuring the pressureassociated with the cryogenically collected hyperpolarized gas duringthe thawing and storing steps, said measuring step measuring thepressure at a location in the exit flow path plumbing which is locateddownstream of the cold finger; and releasing the thawed sample as a gasfrom the cold finger when the measured pressure reaches a predeterminedvalue as determined by said step of measuring.
 9. A method according toclaim 8, wherein a major portion of said hyperpolarized gas transitionsfrom a frozen solid sample directly into a liquid phase corresponding tothe pressure in said cold finger during said thawing step, and whereinsaid releasing step is in response to the opening of a valve downstreamof the cold finger in the hyperpolarizer and wherein the predeterminedpressure is at least about 1 atm.
 10. A method according to claim 8,wherein the cold finger has two spaced apart shut off valves associatedtherewith, at least one of which is open during the thawing step.
 11. Amethod according to claim 8, wherein said hyperpolarized gas samplecomprises hyperpolarized ¹²⁹Xe.